From Mouse to Man

What the latest basic science research is telling us about the human mind

A gene for anxiety, depression and posttraumatic stress disorder; FKBP5

Why some people develop PTSD and others don't; genetics.
Everyone experiences stress and unhappiness at some points in their lives. For most people, these unpleasant episodes are transient but for others they are associated with the development of conditions such as depression, anxiety and posttraumatic stress disorder. A key challenge for scientists is to try to understand why only some people will develop these disorders.

Nature, nurture and interactions between the two are all suspected. It is well established that many psychiatric conditions have a genetic component and that environmental conditions will influence those genes. Posttraumatic stress disorder (PTSD) is an excellent example of this; people carrying genes that increase the likelihood of them developing posttraumatic stress disorder will still have to experience significant stress before the disorder develops.

Recent search has identified one such gene, the rather unattractively titled FKBP5, or to give it it's full name, FK506 binding protein number 5. Perhaps unsurprising, FKBP5 is part of the body's stress-sensing system, the hypothalamic-pituitary-adrenal axis (HPA axis). In response to stress, this system produces a hormone, cortisol, which is central to many of the body's biological responses to stress. Some, but not all, studies suggest that the HPA axis is overactive in PTSD sufferers. Most interestingly, some prospective studies suggest that this increased stress reactivity may exist prior to, and thus potentially explain the development of, PTSD.

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Everyone carries the FKBP5 gene but, like almost all genes, subtle variants of FKBP5 occur in some people. These variations, called SNPs (single nucleotide polymorphisms) can cause changes in how that gene functions. A number of recent studies have shown that some variants of FKBP5 are associated with changes in the body's normal response to stress as well as PTSD, depression and perhaps most intriguingly, increased responses to antidepressant treatment.

How these variations in FKBP5 affect its function and its role in the stress-sensing system is still being worked out, but one common theme is that the hormonal response to stress is different in persons carrying FKBP5 variants.

Digging deeper into some of these studies provides significant insight into environmental influence on disease genes. Researchers at Emory University, led by Kerry Ressler M.D. Ph.D, have identified four variants of the FKBP5 gene that are more commonly found in people who suffer from posttraumatic stress disorder. Many unfortunate factors contribute toward the development of posttraumatic stress disorder, with a history of child abuse being one of the most significant. Importantly, the genetic variants of FKBP5 are found in PTSD patients with a history of child abuse, but not PTSD patients who do not have a history of child abuse, suggesting a gene- environment interaction during childhood that can predict the development of posttraumatic stress disorder.

Much of the information about the genetics of FKBP5 has come from the Grady Trauma Project, an ongoing project at Emory University in Atlanta, GA. The project aims to identify the genetic and environmental factors that contribute to the development of posttraumatic stress disorder. Large, progressive studies such as these are vital to our understanding of how nature and nurture interact in the development of disease.

FKBP5 is only a small part of the stories of anxiety, depression and posttraumatic stress disorder but it's significant because it clearly interacts with environmental conditions. This theme of nature-nurture interactions is something I expect to become more prominent in genetic research over the next few years. In addition to identifying genetic risk, such research will also identify molecular pathways that can be targeted by drug development.

Philip M. Newton, Ph.D. is a Neuroscience Lecturer at Swansea University Medical School in the United Kingdom.

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